2. Academic Validation
  3. Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1G93A amyotrophic lateral sclerosis (ALS) mice

Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1G93A amyotrophic lateral sclerosis (ALS) mice

  • Br J Pharmacol. 2025 Feb 13. doi: 10.1111/bph.17448.
Laura Moreno-Martinez 1 2 3 4,  Núria Gaja-Capdevila 1 5,  Laura Mosqueira-Martín 1 6 7,  Mireia Herrando-Grabulosa 1 5,  Laura Rodriguez-Gomez 7,  Klaudia Gonzalez-Imaz 1 6 7,  Ana C Calvo 1 2 3 4,  Maialen Sagartzazu-Aizpurua 8,  Leticia Moreno-García 1 2 3 4,  Jose Manuel Fuentes 1 9 10,  Abraham Acevedo-Arozena 1 11,  Jesús María Aizpurua 8 12,  José Ignacio Miranda 8 12,  Adolfo López de Munain 1 6 7 12 13,  Ainara Vallejo-Illarramendi 1 6 7 12,  Xavier Navarro 1 5,  Rosario Osta 1 2 3 4,  Francisco Javier Gil-Bea 1 7 12 14 15
Affiliations

Affiliations

  • 1 Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
  • 2 LAGENBIO, Faculty of Veterinary, University of Zaragoza, Zaragoza, Spain.
  • 3 Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), Zaragoza, Spain.
  • 4 AgriFood Institute of Aragon-IA2 (UNIZAR-CITA), Zaragoza, Spain.
  • 5 Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain.
  • 6 Group of Neurosciences, Departments of Pediatrics and Neuroscience, Faculty of Medicine and Nursing, University of Basque Country (UPV/EHU), San Sebastian, Spain.
  • 7 Department of Neuroscience, BioGipuzkoa Health Research Institute (IIS BioGipuzkoa), San Sebastian, Spain.
  • 8 Department of Organic Chemistry-I, Korta Research Center, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
  • 9 Department of Biochemistry and Molecular Biology and Genetics, Faculty of Nursing and Occupational Therapy, University of Extremadura, Cáceres, Spain.
  • 10 Instituto de Investigación Biosanitaria de Extremadura (INUBE), Cáceres, Spain.
  • 11 Research Unit, Canarias University Hospital, ITB-ULL, Tenerife, Spain.
  • 12 Miramoon Pharma, San Sebastian, Spain.
  • 13 Donostia University Hospital, San Sebastian, Spain.
  • 14 IKERBASQUE Basque Foundation for Science, Bilbao, Spain.
  • 15 Department of Health Sciences, Public University of Navarra, Pamplona, Spain.
PMID: 39947630 DOI: 10.1111/bph.17448
Abstract

Background and purpose: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons, characterized by dysregulated CA2+ influx and buffering in early ALS-affected motor neurones. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular CA2+, as a therapeutic target.

Experimental approach: A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the superoxide dismutase 1 (SOD1)G93A mouse model of ALS. Different outcomes were used to assess treatment efficacy, including electrophysiology, histopathology, neuromuscular function and survival.

Key results: Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability and favourable in vitro pharmaco-toxicological profile. Chronic administration of MP-010 to SOD1G93A mice produced preservation of motor nerve conduction, with the 61-mg·kg-1 dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates and significant preservation of motor neurones in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10 days compared to vehicle.

Conclusions and implications: FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.

Keywords

ALS; FKBP12; RyR; SOD1; calcium.

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